Enantio‐ and Diastereoselective 1,2‐Additions to α‐Ketoesters with Diborylmethane and Substituted 1,1‐Diborylalkanes

The catalytic enantioselective synthesis of boronate‐substituted tertiary alcohols through additions of diborylmethane and substituted 1,1‐diborylalkanes to α‐ketoesters is reported. The reactions are catalyzed by readily available chiral phosphine/copper(I) complexes and produce β‐hydroxyboronates containing up to two contiguous stereogenic centers in up to 99:1 e.r. and greater than 20:1 d.r. The utility of the organoboron products is demonstrated through several chemoselective functionalizations. Evidence indicates the reactions occur via an enantioenriched α‐boryl‐copper‐alkyl intermediate.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

Reaction of Pyrimidinonethione Derivatives: Synthesis of N‐Methyl‐2‐Hydrizinopyrimidine‐4‐One,Thiazolo[3,4‐b] N‐Methylpyrimidinone; 2‐(1‐Pyrazolonyl) N‐Methylpyrimidine‐4‐one and 2‐Hydrazino‐N‐Methyl Pyrimidine‐4‐One Derivatives

6‐Aryl‐5‐cyano‐4‐pyrimidinone‐2‐thion derivatives 1a‐c reacted with methyl iodide (1:2) to give the corresponding 2‐S,N‐dimethyl pyrimidine‐4‐one derivatives 2a‐c . Compounds 2a‐c were in turn, reacted with hydrazine hydrate to give the sulfur free reaction products 3a‐c . These reaction products were taken as the starting materials for the synthesis of several new heterocyclic derivatives. Reaction of 3a‐c with acetic anhydride and formic acid gave pyrimido triazines 4a‐c and 7a‐c , respectively. Their reactions with active methylene containing reagents gave the corresponding 2‐(1‐pyrazonyl)‐N‐methyl pyrimidine derivatives 9a‐c and 10a‐c , respectively. Their reactions with aromatic aldehydes afforded the corresponding 2‐hydrazono pyrimidine derivatives 11a‐c . The structure of these reactions products were established based on both elemental analysis and spectral data studies.     

2‐(Pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone and 2‐phenyl­sulfanyl‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone

The structure of 2‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, C₁₄H_12.95Cl_0.05NO₂, (I), is actually a 0.95:0.05 mixture including 2‐chloro‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone as a minor impurity, but (I) was resolved as a single molecule containing a Cl atom with 5% occupancy at the 3‐position. Compound (I) was prepared from the fully chloro‐substituted analogue in an attempt to produce the disubstituted pyrrolidinyl derivative. 2‐Phenyl­sulfanyl‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, C₂₀H₁₇NO₂S, (II), was also prepared from 2‐chloro‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, using a strong exocyclic nucleophile. The structure of (II) differs from previous structures of 2,3‐di­chloro‐1,4‐naphtho­quinone and its derivatives in that the naphtho­quinone ring is non‐planar.     

(±)‐6‐tert‐Butyl‐8‐hydroxymethyl‐2‐­phenyl‐4H‐1,3‐benzodioxin and 2,2,2′,2′,6,6′‐hexamethyl‐8,8′‐methylenebis(4H‐1,3‐benzodioxin)

Two compounds containing 1,3‐benzodioxin groups are reported, namely (±)‐6‐tert‐butyl‐8‐hydroxy­methyl‐2‐phenyl‐4H‐1,3‐benzodioxin, C₁₉H₂₂O₃, (I), and 2,2,2′,2′,6,6′‐hexamethyl‐8,8′‐methyl­enebis(4H‐1,3‐benzodioxin), C₂₃H₂₈O₄, (II).The hydroxy groups of neighbouring mol­ecules in (I) are hydrogen bonded to each other, giving rise to double‐row chains. The mol­ecule in (II) adopts a `butterfly' conformation, with the O atoms in distal positions. In both compounds, the dioxin rings are in distorted half‐chair conformations.     

4‐Ethynyl‐4‐hydroxycyclohexan‐1‐one and 4‐ethynyl‐4‐hydroxy‐2,3,5,6‐tetramethylcyclohexa‐2,5‐dien‐1‐one

The title compounds, C₈H₁₀O₂, (I), and C₁₂H₁₄O₂, (II), occurred as by‐products in the controlled synthesis of a series of bis­(gem‐alkynols), prepared as part of an extensive study of synthon formation in simple gem‐alkynol derivatives. The two 4‐(gem‐alkynol)‐1‐ones crystallize in space group P2₁/c, (I) with Z′ = 1 and (II) with Z′ = 2. Both structures are dominated by O—H?O=C hydrogen bonds, which form simple chains in the cyclo­hexane derivative, (I), and centrosymmetric dimers, of both symmetry‐independent mol­ecules, in the cyclo­hexa‐2,5‐diene, (II). These strong synthons are further stabilized by C[triple‐bond]C—H?O=C, C_methylene—H?O(H) and C_methyl—H?O(H) interactions. The direct intermolecular interactions between donors and acceptors in the gem‐alkynol group, which characterize the bis­(gem‐alkynol) analogues of (I) and (II), are not present in the ketone derivatives studied here.     

Co‐crystals of 3‐deoxy‐3‐fluoro‐α‐d‐glucopyranose and 3‐deoxy‐3‐fluoro‐β‐d‐glucopyranose

3‐Deoxy‐3‐fluoro‐d ‐glucopyranose crystallizes from acetone to give a unit cell containing two crystallographically independent molecules. One of these molecules (at site A) is structurally homogeneous and corresponds to 3‐deoxy‐3‐fluoro‐β‐d ‐glucopyranose, C₆H₁₁FO₅, (I). The second molecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3‐deoxy‐3‐fluoro‐α‐d ‐glucopyranose, (II); treatment of the diffraction data using partial‐occupancy oxygen at the anomeric center gave a high‐quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of α‐ and β‐anomers at site B appears to be accommodated in the lattice because hydrogen‐bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. Cremer–Pople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [θ_(I) = 3.85 (15)° and θ_(II) = 6.35 (16)°], but the general direction of distortion is similar in both structures [ϕ_(I) = 67 (2)° (B_C1,C4) and ϕ_(II) = 26.0 (15)° (^C3TB_C1); B = boat conformation and TB = twist‐boat conformation]. The exocyclic hydroxymethyl (–CH₂OH) conformation is gg (gauche–gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, deoxy and fluorine‐substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns.     

1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计、合成与HIV整合酶抑制活性评价

一价铜催化端炔与叠氮化物的1, 3-环加成反应是一种快速构建小分子库并筛选其可能性质的的主要方法。本文报道了1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计与合成。在该类化合物中,疏水性与亲水性片段通过Click反应有效地连接。所设计化合物8和12的结构通过光谱手段进行了表征;其可能的HIV整合酶抑制活性也进行了筛选。     

Functional Ionic Liquids Promoted Double Michael Reaction of Benzofuran‐3‐one or 1‐Indone and Symmetric Dienones: Construction of Spiro[benzofuran‐2,1’‐cyclohexane]‐3‐one or Spiro[cyclohexane‐1,2’‐indene]‐1’,4(3’H)‐dione Derivatives

The double Michael reactions between benzofuran‐3‐one or 1‐indone and symmetric dienones in the presence of catalytic ionic liquids were successfully developed and spiro[benzofuran‐2,1’‐cyclohexane]‐3‐one or spiro[cyclohexane‐1,2’‐indene]‐1’,4(3’H )‐dione derivatives containing a spiro quaternary stereogenic center, which widely exist in biologically active products and building blocks in organic synthesis, were obtained in excellent yields (up to 99%). This catalytic system was also extended to the double Michael reaction of less reactive 1‐indone and the desired products were also obtained in 31%‐62% yields. The catalytic system was highly active and efficient for a broad of substrates under mild conditions.     

Trifluoroacetic Anhydride Promoted Copper(I)‐Catalyzed Interrupted Click Reaction: From 1,2,3‐Triazoles to 3‐Trifluoromethyl‐Substituted 1,2,4‐Triazinones

A copper(I)‐catalyzed interrupted click reaction in the presence of trifluoroacetic anhydride has been developed, wherein an N‐trifluoroacetyl group is used to accelerate the ring‐opening of the putative 5‐copper(I) triazolide intermediate. Under the optimized reaction conditions, a broad range of azides and alkynes were found to participate in this transformation, thus affording 3‐trifluoromethyl‐substituted 1,2,4‐triazinones in moderate to excellent yields. The reaction has proven to be compatible with a variety of electron‐withdrawing and electron–donating groups, halogens, and nitrogen‐ and sulfur‐containing heterocycles, as well as pharmaceutically relevant molecules.     

Copper‐Free Huisgen Cycloaddition for the 14‐3‐3‐Templated Synthesis of Fusicoccin‐Peptide Conjugates

Mid‐sized molecules have emerged as an attractive chemical space and potentially provide a robust basis for the development of synthetic agents to control intracellular protein interactions. However, the limited cell permeability and chemical tractability of such agents remain to be addressed. We envisioned that target‐templated synthesis of such mid‐sized molecules might provide a solution. Here, we exploited a copper‐free Huisgen cycloaddition for template synthesis using a peptide fragment containing a 4,8‐diazacyclononyne (DACN) moiety and an azide‐containing fusicoccin derivative in the presence or absence of recombinant 14‐3‐3ζ protein in vitro. Time‐course changes in the yield of products demonstrated that the reaction was accelerated in the presence of 14‐3‐3 and one of the regioisomers was generated predominantly, supporting the template effect.     

Construction of Nitrogen‐Containing 9‐Membered Ring Epoxy Vinyl Ethers via Gold(I)‐Catalyzed Intramolecular Cyclization Reactions of Acyclic 5‐Aza‐2,3‐epoxy‐7‐yn‐1‐ols

A series of substituted nitrogen‐containing 9‐membered epoxy vinyl ethers has been constructed from easily available 5‐aza‐2,3‐epoxy‐7‐yn‐1‐ols. Attack of the hydroxyl group onto the gold(I)‐activated alkyne gave the postulated 9‐membered allylic vinyl ether gold intermediate which underwent protodeauration affording the 9‐membered epoxy vinyl ethers.     

5,5′‐Di‐tert‐butyl‐2,2′‐di­hydroxy‐3,3′‐methyl­enedibenz­aldehyde and 6,6′‐di‐tert‐butyl‐8,8′‐methyl­ene­bis­(spiro­[4H‐1,3‐benzodioxin‐2,1′‐cyclo­hexane])

Two related compounds containing p‐tert‐butyl‐o‐methyl­ene‐linked phenol or phenol‐derived subunits are described, namely 5,5′‐di‐tert‐butyl‐2,2′‐di­hydroxy‐3,3′‐methyl­ene­di­benz­aldehyde, C₂₃H₂₈O₄, (I), and 6,6′‐di‐tert‐butyl‐8,8′‐methyl­ene­bis­(spiro­[4H‐1,3‐benzo­di­oxin‐2,1′‐cyclo­hexane]), C₃₅H₄₈O₄, (II). Both compounds adopt a `butterfly' shape, with the two phenol or phenol‐derived O atoms in distal positions. Phenol and aldehyde groups in (I) are involved in intramolecular hydrogen bonds and the two dioxin rings in (II) are in distorted half‐chair conformations.     

Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α,β‐Unsaturated Pyrazoleamides†

(E)‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1Z,3Z)‐dienolates as the major in the presence of a copper(I)‐(R)‐DTBM‐SEGPHOS catalyst and Et₃N, which react with aldimines to afford syn‐vinylogous products as the major diastereoisomers in high regio‐ and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)‐(1Z,3Z)‐dienolates to copper(I)‐(1Z,3E)‐dienolates. (Z)‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1Z,3Z)‐dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)‐β,γ‐unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)‐catalyzed asymmetric vinylogous Mannich‐Type reaction and anti‐vinylogous products were obtained. In the previous reaction, copper(I)‐ (1Z,3E)‐dienolates were generated through α‐deprotonation, which might form an equilibrium with (E)‐allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)‐α,β‐unsaturated pyrazoleamides lead to syn‐products and (E)‐β,γ‐unsaturated pyrazoleamides lead to anti‐products. Finally, by use of (E)‐β,γ‐unsaturated pyrazoleamide, (E)‐α,β‐unsaturated pyrazoleamide, (R)‐DTBM‐SEGPHOS, and (S)‐DTBM‐SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three‐step reaction sequence, all four stereoisomers of N‐Boc‐2‐Ph‐3‐Me‐piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.     

Two tautomeric forms of 2‐amino‐5,6‐dimethylpyrimidin‐4‐one

Derivatives of 4‐hydroxypyrimidine are an important class of biomolecules. These compounds can undergo keto–enol tautomerization in solution, though a search of the Cambridge Structural Database shows a strong bias toward the 3H‐keto tautomer in the solid state. Recrystallization of 2‐amino‐5,6‐dimethyl‐4‐hydroxypyrimidine, C₆H₉N₃O, from aqueous solution yielded triclinic crystals of the 1H‐keto tautomer, denoted form (I). Though not apparent in the X‐ray data, the IR spectrum suggests that small amounts of the 4‐hydroxy tautomer are also present in the crystal. Monoclinic crystals of form (II), comprised of a 1:1 ratio of both the 1H‐keto and the 3H‐keto tautomers, were obtained from aqueous solutions containing uric acid. Forms (I) and (II) exhibit one‐dimensional and three‐dimensional hydrogen‐bonding motifs, respectively.     

3,5‐Bis{3‐[4‐(dimethylamino)phenyl]prop‐2‐enylidene}‐1‐methyl‐4‐piperidone and 3,5‐bis[3‐(4‐methoxyphenyl)prop‐2‐enylidene]‐1‐methyl‐4‐piperidone: potential biophotonic materials

The structures of the title compounds, C₂₈H₃₃N₃O, (I), and C₂₆H₂₇NO₃, (II), together with their two‐photon absorption properties and fluorescence activities are reported. Molecules of (II) reside on crystallographic mirror planes containing the piperidone C=O group and N‐methyl H atoms. Because of the conjugation between the donor and acceptor parts, the central heterocycle in both (I) and (II) exhibits a flattened boat conformation, with deviations of the N atom and the opposite C atom from the planar fragment. The dihedral angles between the coplanar heterocyclic atoms and terminal C₆ rings are less than 20° in both (I) and (II). In (I), the N‐methyl group of the ring occupies an equatorial position, but in (II) it is positioned in an axial site. In the crystal structure of (I), weak intermolecular C—H...π(arene) and C—H...O steric contacts link the molecules along the a axis. In the crystal structure of (II), molecules form stacks along the b axis.     

Reactions of 4‐Hydroxyquinolin‐2(1H)‐ones with Acenaphthoquinone: Synthesis of New 1,2‐Dihydroacenaphthylene‐spiro‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones)

Reaction of four equivalents of 4‐hydroxyquinolin‐2(1H)‐ones with one equivalent of acenaphthoquinone in absolute ethanol, containing catalytic triethylamine, gave 3,3′,3″,3?‐(1,2‐dihydroacenaphthylene)‐1,1,2,2‐tetrayl‐tetrakis(4‐hydroxyquinolin‐2(1H)‐ones) in a good to excellent yields. The structures of the products were elucidated by ¹H NMR, ¹³C NMR, NMR, IR, mass spectra, and elemental analyses.     

Enantio‐ and Diastereoselective Cyclopropanation of 1‐Alkenylboronates: Synthesis of 1‐Boryl‐2,3‐Disubstituted Cyclopropanes

A novel, highly enantio‐ and diastereoselective synthesis of 1‐boryl‐2,3‐disubstituted cyclopropanes has been developed by means of the cyclopropanation of alkenylboronates with ethyl diazoacetate in the presence of catalytic amounts of a chiral copper(I) complex. The products can also be directly accessed from alkynes through an operationally simple, sequential hydroboration–cyclopropanation protocol. The resulting enantioenriched 1‐boryl‐2,3‐disubstituted cyclopropanes are versatile synthetic intermediates that undergo further transformations at the carbon–boron bond.     

Difur­aza­no­[3,4‐b:3′,4′‐f]‐4,5‐di­aza‐1,8‐dioxa­cyclo­dodecine and an acyclic analogue

The novel title fur­azan‐containing macrocycle (systematic name: 6,9,14,17‐tetraoxa‐2,3,5,7,16,18‐hexa­aza­tri­cyclo­[13.3.0.0^4,8]­octadeca‐4,7,15,18‐tetraene), C₈H₁₀N₆O₄, (I), is the first macrocycle where the fur­azan rings are connected via a hydrazine group. In spite of the strain in the 12‐membered macrocycle of (I), the geometry of the fur­azan fragment is the same in (I) and in its acyclic analogue 1,8‐bis(5‐amino­fur­azan‐4‐yl­oxy)‐3,6‐dioxaoctane, C₁₀H₁₆N₆O₆, (II). In both compounds, the participation of the fur­azan rings in intermolecular hydrogen bonding equalizes the N—O bonds within the fur­azan rings, in contrast with rings which do not participate in such interactions.     

The effect of Cl...π interactions on the conformations of 4‐chloro‐5‐(2‐phenoxyethoxy)phthalonitrile and 4‐chloro‐5‐[2‐(pentafluorophenoxy)ethoxy]phthalonitrile

4‐Chloro‐5‐(2‐phenoxyethoxy)phthalonitrile, C₁₆H₁₁ClN₂O₂, (I), and 4‐chloro‐5‐[2‐(pentafluorophenoxy)ethoxy]phthalonitrile, C₁₆H₆ClF₅N₂O₂, (II), show different types of electrostatic interaction. In (I), the phenoxy and phthalonitrile (benzene‐1,2‐dicarbonitrile) moieties are well separated in an open conformation and intermolecular C—H...π interactions are observed in the crystal packing. On the other hand, in (II), the pentafluorophenoxy moiety interacts closely with the Cl atom to form a folded conformation containing an intramolecular halogen–π interaction.